Sturge-Weber syndrome causes capillary malformations in the brain. They occur in the brain’s leptomeninges, which comprise the arachnoid mater and pia mater.

A person born with a port-wine birthmark on his or her face and eyelid(s) has an 8 to 15 percent chance of being diagnosed with Sturge-Weber syndrome. The rare disorder causes malformations in certain regions of the body’s capillaries (small blood vessels). Port-wine birthmarks appear on areas of the face affected by these capillary malformations.

Aside from the visible symptoms of Sturge-Weber, there are also some more subtle and worrisome ones. Sturge-Weber syndrome can be detected by magnetic resonance imaging (MRI). Such images can reveal a telltale series of malformed capillaries in regions of the brain. Brain capillary malformations can have potentially devastating neurological consequences, including epileptic seizures.

Frustratingly, since doctors first described Sturge-Weber syndrome over 100 years ago, the relationship between brain capillary malformations and seizures has remained somewhat unexplained. In 2013, a Johns Hopkins University team found a GNAQ R183Q gene mutation in about 90 percent of sampled Sturge-Weber patients. However, the mutation’s effect on particular cells and its relationship to seizures still remained unknown.

But recently, some new light has been shed on the mystery. At Boston Children’s Hospital, Sturge-Weber patients donated their brain tissue to research after it was removed during a drastic surgery to treat severe epilepsy. An analysis of their tissue, funded by Boston Children’s Translational Neuroscience Center (TNC), has revealed the cellular location of the Sturge-Weber mutation. The discovery brings new hope of finding ways to improve the lives of those with the disorder.

The reality of Sturge-Weber syndrome

Anna Pinto, MD, PhD, a neurologist and a co-author of the recent findings, knows firsthand how people are affected by Sturge-Weber syndrome.

At the Boston Children’s Sturge-Weber Syndrome Clinic, she sees dozens of people with Sturge-Weber each year. In addition to port-wine birthmarks and neurological abnormalities, Sturge-Weber can also cause developmental delays, motor skill impairment and varying degrees of glaucoma.

Some of her patients feel like their port-wine birthmark is disfiguring. Others suffer extremely severe, life-threatening bouts of epilepsy.

“Sturge-Weber patients with brain capillary malformations have up to a 90 percent risk of epileptic seizures,” explains Pinto.

Hemispherectomy is a last-resort surgical procedure to treat severe epilepsy. It is reserved for the most serious of cases. The surgery disconnects the brain’s two cerebral hemispheres. In people with debilitating epilepsy, hemispherectomy performed on the affected side of their brain can sometimes cure their seizures.

Although it’s a drastic measure, the brain has an amazing ability to adapt. Some people manage to have positive cognitive outcomes.

Two people with Sturge-Weber syndrome, who were experiencing severe cases of epilepsy that could not be medically managed, recently underwent hemispherectomies at Boston Children’s. Their families opted to turn the rare surgeries into extraordinary opportunities for research. Following both hemispherectomies, researchers were permitted to analyze brain tissue removed from the patients.

A Rhode Island family is fighting to keep their young daughter’s epilepsy at bay. Brielle was diagnosed with Sturge-Weber syndrome soon after she was born. Read Brielle’s story.

Pinpointing the genetic culprit

Their tissue has established the first-ever patient-derived laboratory cultures of Sturge-Weber brain cells. A study of the tissue by Boston Children’s researchers discovered the GNAQ R183Q mutation is predominantly found in the brain’s malformed blood vessel cells. These mutated cells — called endothelial cells — may be responsible for triggering neurological dysfunction in people with Sturge-Weber.

“With the results of these two studies, we speculate that mutated endothelial cells in the skin and brain of people with Sturge-Weber may spark dysfunction of other surrounding cells, which can then catalyze tissue overgrowths on the face and severe neurological instability in the brain,” says Bischoff.

The Sturge-Weber mutation occurs after conception and is not hereditary. Known as a somatic mutation, the genes in one cell become altered at some point during a person’s development. As a result, the gene mutation spreads through cell division.

Studies at Boston Children’s have discovered the Sturge-Weber gene mutation in the endothelial cells of port-wine birthmarks and brain capillary malformations. These cells make up the endothelium, which lines the inside of blood vessels.

“The high frequency of GNAQ mutations found in the affected brain’s endothelial cells could perhaps correlate to how early this gene mutation occurs as an individual is developing,” says Bischoff. “Additional studies might help us develop earlier ways of screening for Sturge-Weber before seizures can begin to take their toll.”

The brain samples have already proved invaluable thanks to these initial findings. In the future, cells derived from these patients’ brain samples will continue to provide new investigational opportunities for Bischoff and her collaborators, as they continue their mission to understand Sturge-Weber syndrome.